Male sexual behavior is composed of proceptive and consummatory behaviors. The proceptive behaviors include the awareness of the presence of a receptive female, the pursuit of that female and the positioning of the body (mounting) to allow insertion of the penis into the vagina. This latter behavior, termed intromission, as well as its prerequisite erection of the penis and eventual ejaculation, are the consummatory components of masculine sexual behavior. The accomplishment of ejaculation requires the entire repertoire of the aforementioned behaviors. It is dependent upon the close coordination of sensory and motor components of the nervous system which are coordinated at the levels of the brain and by spinal reflexes.
Male sexual behavior is steroid-dependent and in most mammals testosterone, released by the Leydig cells of the testes, is the hormone involved in permitting the expression of masculine behavior. In sexually experienced male rats, castration results in a gradual diminution and an eventual extinction of masculine sexual behavior. Replacement of the hormone testosterone completely prevents the loss of masculine sexual behavior [Malmnas, Acta Physiologica Scand. (Suppl. 395): 9-46, 1973; Damassa et al, Hormones and Behavior 8: 275-286, 1977]. Additionally, if after castration masculine sexual behavior is allowed to wane prior to the initiation of testosterone replacement, testosterone replacement can restore the full expression of the behavior [Davidson et al, in S. Levine (Ed.) Hormones and Behavior, Academic Press, New York, 1972, pp. 63-103].
Three lines of evidence indicate that the proceptive components of masculine sexual behavior are dependent upon the aromatization in the brain of testosterone to estradiol. First, it has now been conclusively demonstrated that the blockade of the conversion of testosterone to estradiol with aromatase inhibitors or the blockade of estrogen actions with antiestrogens antagonize the effects of testosterone on masculine sexual behavior. Consistent with this notion of testosterone metabolism into estradiol which activates masculine sexual behavior is the distribution of the enzyme, aromatase. In mammals, aromatase is reported to be concentrated in the preoptic area, the hypothalamus, and the amygdala brain regions known to mediate the effects of testosterone on masculine sexual behavior. For representative literature, see: N. J. MacLusky, A. Philip, C. Hurlburt and F. Naftolin, in Metabolism of Hormonal Steroids in the Neuroendocrine Structures, Eds. F. Celotti, F. Naftolin and L. Martini, Raven Press, Vol. 13, 1984, pp. 103--116; B. S. McEwen, Science 211: 1303--1311, 1981; Beyer et al, Hormones and Behavior 7: 353-363, 1976.
Second, following the systemic administration of testosterone, estradiol appears as the major androgen metabolite in regions of the brain known to mediate masculine sexual behavior. In one study of Rhesus monkeys, [.sup.3 H]-testosterone was administered systemically and sections of the brain were extracted to determine the steroid metabolites present. In the hypothalamus, preoptic area and amygdala, 50% or more of the radioactivity was reported to be estradiol, while in other brain structures, the radioactivity remained as testosterone. In contrast, in peripheral tissues such as the seminal vesicles, glans penis and the prostate gland, dihydrotestosterone was the major metabolite (R. W. Bonsall et al, Life Sciences 33: 655-663, 1983). In a subsequent study, which more extensively evaluated testosterone metabolism in brain regions, only the hypothalamus, preoptic area and amygdala were found to form estradiol significantly (61, 43 and 64%, respectively). All other brain areas evaluated contained either no estradiol or less than 10% of the recovered steroids (R. P. Michael et al, Endocrinology 118: 1935-1944, 1986). Finally, the amount of estradiol bound to nuclear receptors in the preoptic area-hypothalamus is directly related to the level of testosterone in the serum, suggesting that the source of estradiol bound to its receptor in this brain region is circulating testosterone (L. C. Krey et al, Brain Res. 193: 277-283, 1980).
Third, estradiol stimulates the proceptive components of masculine sexual behavior. Pfaff (J. Comp. Physiol. Psych. 73: 349-358, 1970) administered estradiol benzoate systemically (10 .mu.g/day) for 9 to 11 days to castrated male rats and observed that estradiol increased mounting, intromissions and ano-genital sniffing and reduced mounting latency to levels comparable to that observed following the administration of testosterone propionate (200 .mu.g/day). Sodersten (Hormones and Behavior 4: 247-256, 1973) administered estradiol benzoate (100 .mu.g/day) for 24 to 28 days to male rats castrated 6 weeks previously and found that mounts and intromissions were equivalent to those observed following similar treatment with testosterone propionate (100 .mu.g/day). Ejaculations were less affected by estradiol benzoate then by testosterone propionate. Gray et al (Physiology and Behavior 24: 463-468, 1980) administered Silastic pellets containing estradiol and evaluated sexual behavior 7 days later. They observed that estradiol stimulated mounting behavior but was less effective than testosterone in enhancing intromissions and ejaculations.
Two studies have evaluated the effects of estradiol implanted into the brain on masculine sexual behavior. In one study, castrated rats were implanted bilaterally with cannulae into the preoptic area and 10 .mu.g of estradiol was delivered through each cannulae every 3 days for 12 days. Estradiol was reported to be more effective than testosterone in inducing mounts and intromissions (Christensen and Clemens, Endocrinology 95: 984-990, 1974). Lisk and Greenwald (Neuroendocrinology 36: 211-217, 1983) reported that preoptic area implantation of estradiol benzoate (no dosage indicated, 23 gauge cannulae used) stimulated mounting, but not intromissions, to levels observed in normal male golden hamsters. While it appears that estradiol acts centrally to stimulate masculine sexual behavior, the two aforementioned studies utilized high drug doses which could readily diffuse out of the brain. Thus, it is not certain from these reports to what extent a central versus peripheral action of estradiol is related to the stimulation of masculine sexual behavior.
Estradiol does not fully restore masculine sexual behavior in castrated male rats. Rather, it stimulates the proceptive components of the behavior. Thus, it is not surprising that in most studies, administration of estradiol alone had less effect on ejaculatory behavior than on mounting and intromission behavior in rats. For representative literature, see: Baum and Vreeburg, Science 182: 283-285, 1973; Christensen and Clemens, Endocrinology 95: 984-990, 1974; Gray et al, Physiology and Behavior 24: 463-468, 1980; Larsson, Sodersten and Beyer, Hormones and Behavior 4: 289-299, 1973; Lisk and Greenwald, Neuroendocrinology 36: 211-217, 1983; Sodersten, Hormones and Behavior 4: 247-256, 1973.
To test the hypothesis that central stimulation by estradiol and peripheral stimulation by dihydrotestosterone were the mechanisms by which testosterone stimulates masculine sexual behavior, several studies have utilized both estradiol and dihydrotestosterone in combination. Larsson et al (Hormones and Behavior 4: 289-299, 1973) reported that, while dihydrotestosterone-treatment of castrated male rats was ineffective alone, in combination with estradiol benzoate it returned each component of masculine sexual behavior to levels observed in normal male rats. DeBold and Clemens (Hormones and Behavior 11: 401-413, 1978) reported that, in castrated male rats, treatment with estradiol benzoate plus dihydrotestosterone induced the complete male sexual behavior pattern, while either hormone alone was much less effective. Finally, Lisk and Greenwald (Neuroendocrinology 36: 211-217, 1983) reported that, while preoptic area implants of estradiol benzoate had little effect on intromission behavior in castrated male rats, the combination of estradiol benzoate (into the preoptic area) and systemic treatment with dihydrotestosterone returned intromission behavior to levels observed in normal intact male rats. They concluded that the combination of central stimulation by estradiol and peripheral stimulation by dihydrotesterone reinstated a behavior equivalent to that stimulated by testosterone.
While it would appear from the available literature that estradiol acts in the brain to stimulate masculine sexual behavior, these data must be considered with some caution. That is, every study which has evaluated estradiol effects on sexual behavior has used routes of administration which deliver the hormone to both the central nervous system and the periphery. Even implants of estradiol into the brain result in a rapid delivery of the hormone to the periphery. Thus, the relative contribution of central versus peripheral effects of estradiol on masculine sexual behavior has not been demonstrated with certainty.
At the present time, estrogens are not used to treat male sexual dysfunctions, primarily because of significant undesirable side-effects. Estrogens are, however, generally administered to control symptoms of menopause; for postmenopausal osteoporosis, dysmenorrhea, menorrhagia, amenorrhea, atrophic vaginitis, ovarian dwarfism and post-partum breast engorgement; in combination with progestins in oral contraceptives; in breast cancer; and in men in prostatic carcinoma. These uses are a reflection of the significant physiological and pharmacological actions of the estrogens, especially on the reproductive organs. Unfortunately, some significant toxic effects, including increased risk of thromboembolism, thrombophlebitis and endometrial carcinoma, are associated with the use of these hormones in therapy. Additionally, in the male, estrogen treatment stimulates gynecomastia, causes testicular regression and feminizes hair growth patterns.
Recently, a chemical delivery system (CDS) has been devised which promises to deliver centrally acting drugs, such as the estrogens, to the brain in a sustained and site-specific manner. In accord with this system, the desired centrally-mediated hormonal effects of the estrogens can be achieved without the high concentrations throughout the body which are believed to be responsible for the significant toxic effects generally associated with use of these drugs. The estrogen-chemical delivery system is generally described in Bodor U.S. Pat. No. 4,479,932 issued to UNIVERSITY OF FLORIDA on Oct. 30, 1984, and more specifically in UNIVERSITY OF FLORIDA's International Application No. PCT/US83/00725 (published under International Publication No. WO83/03968), in Bodor U.S. Pat. No. 4,540,564 issued to UNIVERSITY OF FLORIDA on Sept. 10, 1985, and in copending Bodor U.S. patent application Ser. Nos. 665,940 and 666,210, both filed Oct. 29, 1984. Briefly, according to the estrogen-CDS system, the target estrogen is tethered to a reduced, blood-brain barrier-penetrating lipoidal form of a dihydropyridine.revreaction.pyridinium salt type redox carrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type estrogen/carrier entity prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/estrogen species results in sustained delivery of the estrogen in the brain and facile elimination of the carrier moiety. As stated in the aforementioned U.S. Pat. No. 4,479,932, the rationale for brain delivery of the steroid hormones, e.g. estradiol, at least in part derives from the fact that recent studies of histological mapping of hormone-sensitive and specific steroid-binding cells in the brain have underscored the importance of steroid action in the brain on sexual behavior. Further details of the estrogen-chemical delivery system are given hereinbelow.
More recently, it has been found that the redox carrier-estrogen derivatives described in the aforementioned patents are useful in achieving weight control in mammals; cf. Bodor et al copending U.S. patent application Ser. No. 790,159, filed Oct. 22, 1985, now U.S. Pat. No. 4,617,298. Related literature on the carrier-estrogens reports sustained LH inhibition and sustained reduction of body weight increases (Estes et al, Program, 67th Annual Meeting of the Endocrine Society, Baltimore, MD, p. 52, 1985; Estes et al, 68th Annual Meeting of the Endocrine Society, Anaheim, CA, p. 288, 1986).